Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCBUSKJ)

• DOT Name: E3 ubiquitin-protein ligase pellino homolog 3 (PELI3)
• Synonyms: Pellino-3; EC 2.3.2.27
• Gene Name: PELI3
• Related Disease:
  Non-small-cell lung cancer
  Obesity
  Age-related macular degeneration
• UniProt ID: PELI3_HUMAN
• EC Number: 2.3.2.27
• Pfam ID: PF04710 ; PF20723
• Sequence:
  MVLEGNPEVGSPRTSDLQHRGNKGSCVLSSPGEDAQPGEEPIKYGELIVLGCCEEGGEET
  EAQRGEVTGPRAHSCYNGCLASGDKGRRRSRLALSRRSHANGVKPDVMHHISTPLVSKAL
  SNRGQHSISYTLSRSHSVIVEYTHDSDTDMFQIGRSTENMIDFVVTDTSPGGGAAEGPSA
  QSTISRYACRILCDRRPPYTARIYAAGFDASSNIFLGERAAKWRTPDGLMDGLTTNGVLV
  MHPAGGFSEDSAPGVWREISVCGNVYTLRDSRSAQQRGKLVENESNVLQDGSLIDLCGAT
  LLWRTPAGLLRAPTLKQLEAQRQEANAARPQCPVGLSTLAFPSPARGRTAPDKQQPWVYV
  RCGHVHGYHGWGCRRERGPQERECPLCRLVGPYVPLWLGQEAGLCLDPGPPSHAFAPCGH
  VCSEKTARYWAQTPLPHGTHAFHAACPFCGAWLTGEHGCVRLIFQGPLD
• Function: E3 ubiquitin ligase catalyzing the covalent attachment of ubiquitin moieties onto substrate proteins. Involved in the TLR and IL-1 signaling pathways via interaction with the complex containing IRAK kinases and TRAF6. Mediates 'Lys-63'-linked polyubiquitination of IRAK1. Can activate AP1/JUN and ELK1. Acts as a regulator of innate immunity by mediating 'Lys-63'-linked polyubiquitination of RIPK2 downstream of NOD1 and NOD2, thereby transforming RIPK2 into a scaffolding protein for downstream effectors, ultimately leading to activation of the NF-kappa-B and MAP kinases signaling. Catalyzes 'Lys-63'-linked polyubiquitination of RIPK2 in parallel of XIAP.
• Tissue Specificity: Highly expressed in brain, heart and testis, and at lower level in kidney, liver, lung, placenta, small intestine, spleen and stomach. Isoform 1 is not expressed in lung.
• Reactome Pathway:
  IRAK1 recruits IKK complex (R-HSA-937039)
  IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation (R-HSA-975144)
  Interleukin-1 signaling (R-HSA-9020702)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[1]
Obesity	DIS47Y1K	Strong	Altered Expression	[2]
Age-related macular degeneration	DIS0XS2C	moderate	Genetic Variation	[3]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of E3 ubiquitin-protein ligase pellino homolog 3 (PELI3).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of E3 ubiquitin-protein ligase pellino homolog 3 (PELI3).	[11]

8 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of E3 ubiquitin-protein ligase pellino homolog 3 (PELI3).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of E3 ubiquitin-protein ligase pellino homolog 3 (PELI3).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of E3 ubiquitin-protein ligase pellino homolog 3 (PELI3).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of E3 ubiquitin-protein ligase pellino homolog 3 (PELI3).	[8]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of E3 ubiquitin-protein ligase pellino homolog 3 (PELI3).	[5]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of E3 ubiquitin-protein ligase pellino homolog 3 (PELI3).	[9]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of E3 ubiquitin-protein ligase pellino homolog 3 (PELI3).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of E3 ubiquitin-protein ligase pellino homolog 3 (PELI3).	[12]

References

• [1] PELI3 mediates pro-tumor actions of down-regulated miR-365a-5p in non-small cell lung cancer.Biol Res. 2019 Apr 17;52(1):24. doi: 10.1186/s40659-019-0230-y.
• [2] Genome-wide analysis identifies colonic genes differentially associated with serum leptin and insulin concentrations in C57BL/6J mice fed a high-fat diet.PLoS One. 2017 Feb 7;12(2):e0171664. doi: 10.1371/journal.pone.0171664. eCollection 2017.
• [3] Protective coding variants in CFH and PELI3 and a variant near CTRB1 are associated with age-related macular degeneration?"Yu Y. Souied EH
• [4] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [5] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [6] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [9] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [10] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [11] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [12] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.